Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the production of antinuclear antibodies to ribonucleoproteins and double-stranded DNA (dsDNA). Approximately 1.5 million Americans are affected by this illness, the majority being women. The etiology of SLE is unknown, but several viruses in particular the Epstein-Barr virus (EBV) have been implicated. There is an increase in the frequency of EBV infection observed in SLE patients compared to normal individuals. Epstein-Barr Nuclear Antigen-1 (EBNA-1) is a major antigen involved in viral latency that contains binding sites for viral DNA as well as chromosomes. We previously demonstrated that mice expressing EBNA-1 develop antibodies to dsDNA. The major objective of this proposal is to define the mechanism by which EBNA-1 exposure leads to the production of anti-dsDNA antibodies and whether these anti-dsDNA antibodies are pathogenic and deposit in the kidney. We will also determine whether or not EBNA-1 must complex with eukaryotic DNA in order to elicit an anti-DNA response or whether anti-EBNA-1 antibodies cross-react with dsDNA. Finally, we will address if there are strain specific differences in responsiveness to EBNA-1 and the development of antidsDNA antibodies and if this is mediated by TH1 orTH2 cells.